Malaria is one of the three diseases designated by the WHO as being one of the most important in the world, along with HIV/AIDS and tuberculosis. Each year, malaria kills between 1 and 2 million people and affects approximately 500 million, and can lead to a decrease in growth rate ranging up to 1.3% of the GDP in greatly affected countries. A parasite of the Plasmodium genus, transmitted to humans via a bite from a female mosquito of the Anopheles genus, is responsible for this disease. There are four species responsible for human malaria: P. vivax, P. malariae, P. ovale and P. falciparum. P. vivax and P. falciparum are the most common. Infection with P. falciparum is the most severe and can cause death of the patient during a febrile coma. P. falciparum malaria is very widespread in sub-Saharan Africa, where an extremely high mortality rate can to a large extent be attributed thereto. Worrying signs attest to the spread of P. falciparum malaria to new regions and to its resurgence in areas where it had been eliminated or controlled.
There are only a few molecules active against this disease which are formulated as medicaments, and the emergence of resistance makes the problem of treatment even more acute. It is therefore essential to identify novel molecules which have antimalarial activity.
Among the molecules currently known for their efficacy against malaria, mention may be made of quinine, its derivatives and other compounds: chloroquine, amodiaquine, mefloquine, halofantrine, lumefantrine, and also artemisinin and its derivatives, such as artesunate and arteether or artemether. The most well-known are derived from medicinal plants traditionally used in their country of origin. Quinine is derived from Cinchona spp. and artemisinin is derived from Artemisia annua. 
Some of these molecules can be used either as prophylaxis (prevention when traveling to endemic country) or as therapy (after diagnosis of an infection).
The Plasmodium cycle is very complex: in a simplified manner, after a passage in the liver, the parasite rapidly enters the red blood cells of the affected individual, reproduces therein until it causes them to rupture, and invades the neighboring red blood cells. The disease then manifests itself as a fever which is more or less anarchic at the beginning, and then regular after a few multiplication cycles. Some parasites then evolve into gametocytes. These gametocytes make it possible, firstly, for the cycle to continue in the Anopheles mosquito (they are not digested by the mosquito) and, secondly, for genetic mixing to occur since they determine the gametes, which are required for fertilization.
Molecules such as quinine and artemisinin act during the multiplication phase in red blood cells, the erythrocyte phase which is the symptomatic phase. With regard to molecules which have an anti-gametocytocidal activity, the advantage thereof lies in the potential decrease in the rate of transmission of the disease (infectivity) that these molecules could induce, in a group treatment strategy, and also in the possibility of reducing the phenomena of rapid appearance of resistance linked in part to the levels of circulating gametocytes (demonstrated for sulfadoxine-pyrimethamine (SP), and chloroquine (sensitive strains vs resistant strains)). Despite the advantage of using gametocytocidal treatments, there have been few studies aimed at detecting and rationalizing the use of products of this type. Currently, only a few molecules are known to have this property, these being artemisinin and its derivatives, and primaquine. However, primaquine is not the most suitable molecule for use in this way since it has acute toxicity close to its level of activity.
The antimalarial medicaments are not without side effects, and in particular halofantrine has been associated with cardiac problems and mefloquine can exhibit neurological toxicity.
Most of the antimalarial medicaments have a limited lifetime, and lose their efficacy because of the appearance of resistance phenomena. For example, chloroquine, and also the dihydrofolate reductase inhibitors (sulfadoxine/pyrimethamine: Fansidar®) are no longer active on most plasmodium strains and are no longer used in monotherapy. Resistances have also appeared for the artemisinin derivatives, which are the latest medicaments to have been placed on the market. The antimalarials which have become ineffective or are in the process of rapidly losing their effectiveness have been replaced, according to the WHO directives, by ACTs (artemisinin based combination therapies), which combine an artemisinin derivative and another active molecule. However, the effectiveness of this therapeutic strategy combining two molecules is none the less threatened by artemisinin-resistance phenomena.
Furthermore, even though a considerable effort has been made to make these ACTs affordable for the populations in question, their cost still remains high.
We have identified, from a species of the family Simaroubaceae, Quassia amara (L.), used in traditional medicine throughout north-west Amazonia and as far as Central America against fevers and malaria, a new molecule, Simalikalactone E (SkE), which has been shown to be active against malaria.
An ethnopharmacological investigation and biological tests had made it possible (Vigneron M. et al., Journal of ethnopharmacology, 2005, 98 (3), 351-360; Bertani S. et al., Journal of ethnopharmacology, 2005, 98(1-2), 45-54) to identify preparations based on mature leaves of Quassia amara as advantageous for treating malaria. Antiparasitic tests in vitro and in vivo on mice confirmed the activity of this preparation on malaria (Bertani S. et al., Journal of Ethnopharmacology, 2005, 98(1-2), 45-54). Given the frequency of use of this species in remedies used preventively and curatively against malaria, and the antiparasitic activity detected, a thorough phytochemical study was undertaken in order to identify the components responsible for the activity observed.
A molecule of the quassinoid family with considerable antimalarial activity was isolated from the young leaves of this species: Simalikalactone D (Bertani S. et al., Journal of Ethnopharmacology, 2006, 108(1), 155-157). However, the small amount of Simalikalactone D present in the traditional remedy, prepared from mature leaves of Quassia amara, did not make it possible to justify the activity observed in vitro and in vivo for this remedy. Thus, it was sought to identify other active agents responsible for the activity of Quassia amara against malaria. Several authors have focused on quassinoids as active ingredients for treating malaria or other pathological conditions: Z. Guo et al., Current Medicinal Chemistry, 2005, 2, 173-190; Guido F et al., International Journal for Parasitology, 1998, 28, 635-640; Curcino Vieira I. and Braz-Filho R., Studies in Natural Products, Elsevier, 2006, 33, 433-492. However, no molecule has been retained for developing a medicament.